Rai Georgina, Edwards Lee J, Greenaway Rebecca L, Miller Philip W, Wheelhouse Katherine M P, Crimmin Mark R
Molecular Sciences Research Hub, Imperial College London, 82 Wood Lane, Shepherds Bush, London W12 0BZ, U.K.
GSK Medicines Research Centre, GSK, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, U.K.
ACS Catal. 2024 Dec 18;15(1):343-351. doi: 10.1021/acscatal.4c05324. eCollection 2025 Jan 3.
Aryl aldehydes are key synthetic intermediates in the manufacturing of active pharmaceutical ingredients. They are generated on scale (>1000 kg) through the palladium-catalyzed formylation of aryl bromides using syngas (CO/H). The best-in-class catalyst system for this reaction employs di-1-adamantyl--butylphosphine (cataium A), palladium(II) acetate, and tetramethylethylenediamine. Despite nearly 20 years since its initial report, a mechanistic understanding of this system remains incomplete. Here, we use automation, kinetic analysis, and DFT calculations to develop a mechanistic model for this best-in-class catalyst. We suggest that a combination of the migratory insertion step and dihydrogen activation step is likely involved in the turnover-limiting sequence. The reaction kinetics are responsive to the nature of the substrate, with electron-rich aryl bromides reacting faster and more selectively than their electron-poor counterparts due to the influence of electronics in the migratory insertion step. Our findings add additional insight into the proposed mechanism of palladium-catalyzed formylation of aryl bromides.
芳基醛是活性药物成分制造中的关键合成中间体。它们通过使用合成气（CO/H）对芳基溴进行钯催化甲酰化反应大规模（>1000千克）制备。该反应的一流催化剂体系使用二-1-金刚烷基-叔丁基膦（催化剂A）、乙酸钯（II）和四甲基乙二胺。尽管自最初报道以来已近20年，但对该体系的机理理解仍不完整。在此，我们利用自动化、动力学分析和密度泛函理论计算来建立这种一流催化剂的机理模型。我们认为迁移插入步骤和二氢活化步骤的组合可能参与了限速序列。反应动力学对底物的性质有响应，由于迁移插入步骤中电子效应的影响，富电子芳基溴比贫电子芳基溴反应更快且选择性更高。我们的研究结果为钯催化芳基溴甲酰化反应的 proposed 机理提供了更多见解。 （注：原文中“proposed”疑似拼写错误，可能是“proposed”，这里按照“proposed”翻译为“提出的” ）
